The international microbiological and infectious disease community continues to express serious concern that the continuing evolution of antibacterial resistance could result in bacterial strains against which currently available antibacterial agents will be ineffective. The outcome of such an occurrence could have considerable morbidity and mortality. In general, bacterial pathogens may be classified as either Gram-positive or Gram-negative pathogens. Antibiotic compounds with effective activity against both Gram-positive and Gram-negative pathogens are typically regarded as having a broad spectrum of activity.
In the fight against bacterial infection, beta-lactam antibiotics are essential. Beta-lactams are a broad class of drugs which all have a beta-lactam in their core molecular structure, and typically show effectiveness against a broad spectrum of Gram-positive and Gram-negative bacteria by inhibiting the cell wall synthesis of the bacterium. Because the drug target has no eukaryotic analog, their toxicity is low and they are generally well-tolerated. They remain among the most widely prescribed, safe and effective drugs available to combat bacterial infection. However, their effectiveness is limited by highly resistant infectious strains such as methicillin-resistant Staphylococcus aureus (MRSA) and multi-drug resistant (MDR) strains of Pseudomonas aeruginosa, Acinetobacter baumannii, Escherichia coli, Klebsiella pneumonia, and other Enterobacteriaceae. Such resistant bacteria are major causes of patient morbidity and mortality. Helfand, β-lactams Against Emerging ‘Superbugs’: Progress and Pitfalls, Expert Rev. Clin. Pharmacol. 1(4):559-571 (2008).
Beta-lactam antibiotics, alone and in combination with beta-lactamase inhibitors, continue to represent an essential portion of the antibacterial agents used to combat disease. β-lactam resistance for Gram-negative infections is primarily driven by β-lactamase activity; and the significant dependence on β-lacatam antibiotics has lead to the diversification and increased prevalence of β-lactamases. These β-lactamases are driving resistance to even the newest β-lactam antibiotics. Llarrull, et al., The Future of Beta-Lactams, Current Opinion in Microbiology, 13:551-557 (2010).
A major threat to the efficacy of these drugs is the increasing prevalence of extended-spectrum beta-lactamases (ESBLs). Beta-lactamases are enzymes that are secreted by some bacteria that ring open the beta-lactam portion of a beta-lactam antibiotic and thereby deactivate it. There are currently, four classes of beta-lactamases, denoted Class A, Class B, ClassCand Class D. Class A, ClassCand Class D beta-lactamases are serine beta-lactamase inhibitors, while Class B beta-lactamases are metallo-beta-lactamases (MBLs). Bush & Jacoby, Updated Functional Classification of β-Lactamases, Antimicrobial Agents and Chemotherapy, 54(3):969-976 (March 2010).
To help improve the effectiveness of beta-lactam antibiotics, some beta-lactamase inhibitors have been developed. However, the currently available β-lactamase inhibitors in many instances are insufficient to counter the constantly increasing diversity of β-lactamases. The three most common serine beta-lactamase agents currently used—clavulanic acid, tazobactam and sulbactam—have activity only against certain Class A enzymes, which severely limits their utility. Additionally, beta-lactamase inhibitors currently in clinical trials, such as Avibactam and MK7655 work primarily on Class A and C enzymes, with minimal effectiveness against Class D beta-lactamases. Bebrone, et al., Current Challenges in Antimicrobial Chemotherapy: Focus on β-Lactamase Inhibition, Drugs, 70(6):651-679 (2010). While these agents represent a considerable improvement over the currently available beta-lactamase inhibitors, agents which effectively hit all three serine beta-lactamases are desirable for combating the significant beta-lactam resistance seen today. Currently, there are no approved β-lactamase inhibitors which are effective against Class D β-lactamases, and resistance rates to conventional antibiotics are continuing to rise.
Therefore, there is a need for new β-lactamase inhibitors which are effective against at least D β-lactamases. There is a clear need for new β-lactamase inhibitors which are effective against more than one of Class A, C and/or D β-lactamases.